Respiratory syncytial virus (RSV) is a substantial threat to human health most severely affecting three large populations, infants, young children, and the elderly. Despite the significance of RSV disease in these different populations, there are no vaccines available. The goal of this Phase II STTR project is to continue preclinical testing of a novel RSV vaccine candidate, a candidate unlike any previously tested. This candidate is a virus-like particle (VLP) built on the Newcastle disease virus core proteins, M and NP, and containing the RSV/A F and G proteins inserted into the membrane of the particle. The objective is to determine the potential of VLPs as a vaccine for each of the human populations at risk for serious disease using well-characterized cotton rats models as surrogates for these groups. Specific aim 1: Optimize protective responses in young animals. Children from 2-5 years of age comprise a substantial proportion of RSV illness burden and likely provide a reservoir for infection of newborns. This age group is considered to have less safety constrains than the newborn, 0-6 month age group, and is, most likely, the population where direct vaccination should be seriously considered. Thus for use of VLPs as a vaccine for this population, the immune responses in young animals will be optimized by testing different routes of VLP delivery and options for VLP formulations for cross protection from RSV/B infections. Specific aim 2: Determine the efficacy of maternal immunization in protection of neonates Direct vaccination of neonates is likely ineffective due to the immaturity of their immune system, safety concerns, and inhibition of vaccine protection by maternal antibodies. An alternative approach is protection of newborns from RSV infections through maternal vaccination that will enhance and extend passive transfer of maternal neutralizing antibodies to the fetus. Thus, the protection of cotton rat pups by VLP vaccination of nave and RSV experienced mothers will be measured by virus titer in the pups' lungs and nasal tissue after RSV challenge. In addition, safety of maternal immunization in offspring will be determined by measuring lung histology after RSV challenge of pups. Specific aim 3: Assess efficacy of VLP immunization in elderly populations Elderly immune systems are less vigorous than younger adult populations, thus the responses to a vaccine candidate may be different than those of younger adults. Furthermore, the elderly population has experienced RSV infections in their lifetime. Therefore the protection of both nave and RSV experienced elderly cotton rats by different doses and routes of VLP immunization will be assessed by serum responses and virus titers in lungs after virus challenge to evaluate different strategies of vaccination in this population